tbuckley/cabot-search huggingface dataset:
NIMG-32. POSTPROGRESSION SURVIVAL AND MRI FEATURES AT PROGRESSION IN MGMT-METHYLATED GLIOBLASTOMA FOLLOWING TEMOZOLOMIDE (TMZ) OR CCNU/TMZ THERAPY - AN ANALYSIS OF THE CETEG/NOA-09-TRIAL
Authors: Thomas Zeyen, Daniel Paech, Johannes Weller, Niklas Schäfer, Theophilos Tzaridis, Cathrina Duffy, Louisa Nitsch, Matthias Schneider, Joachim Steinbach, Peter Hau, Uwe Schlegel, Clemens Seidel, Dietmar Krex, Oliver Grauer, Roland Goldbrunner, Pia Zeiner, Ghazaleh Tabatabai, Norbert Galldiks, Walter Stummer, Elke Hattingen, Martin Glas, Alexander Radbruch, Ulrich Herrlinger, Christina Schaub
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION In the randomized CeTeG/NOA-09 trial, combined CCNU/TMZ was superior to TMZ therapy regarding overall survival (OS) in newly diagnosed patients with MGMT-methylated glioblastoma. Using modified RANO criteria, however, progression-free survival (PFS) and pseudoprogression rates were similar in both arms. Exploring the hypothesis of undetected pseudoprogressions being accountable for this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at RANO-defined progression. METHODS 86 CeTeG/NOA-09 patients with progression (modified RANO criteria) and MRI evaluable for standardized T1 and FLAIR volumetry at baseline and progression were included. Patients were further subdivided to short PPS (&amp;lt; 24 months) or long PPS (&amp;gt; 24 months) and a PPS/PFS ratio was calculated. RESULTS In the CCNU/TMZ arm, long PPS patients (n=10) tended to a shorter PFS (median 7.3 months) than short PPS patients in the same arm (n=33, 14 months, p=0.089, logrank test) and long PPS patients in the TMZ arm (n=9, 12.7 months, p=0.21). The mean PPS/PFS ratio in the long PPS group was markedly higher in the CCNU/TMZ arm (5.8) compared to the TMZ arm (3.3, p=0.043, Mann-Whitney test). Patients with long PPS of the CCNU/TMZ arm showed a nonsignificant tendency to a stronger volumetric increase in T1 enhancement (mean delta 6184,86 vs. 697.5 mm³) and FLAIR–T1-enhancement (mean delta 42671 vs 16860 mm³) at progression as compared to long PPS patients of the TMZ arm. CONCLUSION Combining a substantially increased PPS/PFS ratio (long OS despite particularly short PFS according to RANO) with indications for increased contrast enhancement and FLAIR volume at progression, the patients with long PPS in the CCNU/TMZ arm appear to differ from those in the TMZ arm. These observations support the hypothesis that this group (~25% of CCNU/TMZ-treated patients) contained patients with pseudoprogression undetected by modified RANO criteria.
CNSC-32. ACTIN SUBUNIT STRUCTURAL DIVERSITY IN SHH MEDULLOBLASTOMA: IMPLICATIONS FOR CANCER BIOLOGY AND NEURODEVELOPMENT
Authors: Jamie Beaulieu, David Knapp, Daniel Picard, Marc Remke, Abbas Sadikot, Roberto Diaz
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Altered expression of actin subunits is found in multiple cancers. Alpha-cardiac actin (ACTC1) is expressed in sonic hedgehog medulloblastoma (SHH MB) and regulates both cell survival and migration. We hypothesized that cardiac actin has a unique structural and functional role in SHH MB and may be expressed in post-natal granule cell progenitors (GCPs) which share similar gene expression profiles. METHODS Actin subunit protein expression (ACTC1, ACTB, ACTG1, and ACTA2) was evaluated by mRNA expression profiling within established datasets and across MB cell lines by Western blot (WB). Immunofluorescence microscopy was performed to assess intracellular actin subunit localization. The composition of each subunit in filamentous (F-) actin was evaluated. Furthermore immunoprecipitation of filamentous ACTC1 was performed to assess protein-protein interactions. The ratio of F-actin to globular (G-) actin was determined by WB in SHH MB cells exposed to mitotic inhibitor. Cell viability was determined by colony formation following over-expression of dominant-negative mutant ACTC1 (P116C &amp; G247D). RESULTS ACTC1, ACTG1, and ACTB are the predominant actin subunits in SHH MB. Immunofluorescence microscopy demonstrated co-localization of ACTC1 with ACTG1 and ACTB but not ACTA2. ACTC1 showed a unique cortical localization pattern. Post-natal MATH1 positive mouse GCPs (P3-5) demonstrate similar distribution of ACTC1 in cortical F-actin. WB analysis of ACTC1 pulldown from SHH MB cell F-actin fractions showed co-precipitation with ACTG1 and ACTB but not ACTA2. ACTC1 F-actin to G-actin ratio is maintained in cells that show resistance to mitotic inhibition. Expression of mutant ACTC1 G247D resulted in reduced cell survival. CONCLUSIONS ACTC1 subunit is incorporated into F-actin in SHH MB and GCPs. Filamentous ACTC1 forms a protein complex with ACTG1 and ACTB. Disruption of ACTC1 polymerization results in reduced cell survival. These findings suggest a functional role of ACTC1 in both SHH MB and in GCPs which are important in cerebellar development.
SURG-33. RATES OF PRE-OPERATIVE SEIZURE IN PATIENTS WITH MENINGIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Andrew Nguyen, Nolan Brown, Brandon Nguyen, Mark Harris, Rohin Singh, Shane Shahrestani, Julian Gendreau, Ahmed Mohyeldin
Journal: Neuro-Oncology (2022)

Abstract Recent literature has primarily focused on the factors influencing postoperative seizures following resection of meningioma, but many patients also suffer seizures preoperatively. This meta-analysis examined patient demographics, tumor characteristics, and preoperative symptoms to determine which factors are most associated with preoperative seizures. A literature search of Pubmed, Web of Science, and Scopus was conducted. All randomized controlled trials, case-control studies, and cohort studies reporting on preoperative seizure in patients with meningioma were included for analysis. The initial search yielded 4129 total studies, 33 of which were included for quantitative analysis. A total of 8221 patients were analyzed and the rate of preoperative seizure was 26%. Patients were classified as adult vs pediatric and male vs female for analysis. Meningiomas were classified as midline/bilateral vs left-sided vs right-sided, WHO grade 1 vs grade 2-3, greater than 4 cm3 vs less than 4 cm3, and skull base vs non-skull base location. The preoperative signs and symptoms analyzed included presence of headaches, tumor-related edematous change, and neurological deficits. Preoperative seizures were more common in pediatric patients (p&amp;lt; .02) and males (p&amp;lt; .0001). Patients with tumors classified as midline (p&amp;lt; .0001), WHO grade 2-3 (p&amp;lt; .0001), larger than 4 cm3 (p&amp;lt; .0001), and skull base location (p&amp;lt; .0001) were more likely to experience preoperative seizures. Preoperative headaches (p&amp;lt; .0001) were less common in patients with preoperative seizures. Edematous change (p&amp;lt; .0001) and neurological deficits (P&amp;lt; .0001) were more common in patients with pre-operative seizures. On assessment of risk for study bias, no publication bias was detected. This meta-analysis displayed that over 20% of meningioma patients suffer from preoperative seizures. Notably, pediatric patients, patients with midline and skull base meningiomas, and males of all ages were more likely to experience preoperative seizure. Interestingly, patients with preoperative seizures were less likely to experience headaches.
RBIO-07. HIGHER CSF IL-10 CORRELATE WITH BRAIN ATROPHY AFTER WHOLE BRAIN RADIATION THERAPY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Hiroaki Nagashima, Tatsuo Hori, Hirofumi Iwahashi, Kazuhiro Tanaka, Takashi Sasayama
Journal: Neuro-Oncology (2022)

Abstract Whole brain radiation therapy (WBRT) to primary central nervous system lymphoma (PCNSL) correlate with brain atrophy and leukoencephalopathy on serial computed tomography or MRI scans, negatively impacting cognitive function and quality of life. We retrospectively evaluated 53 patients with histologically proven PCNSL who underwent cerebrospinal fluid (CSF) examination including β2-MG, sIL2R, CXCL13, and IL-10 preoperatively. All patients were newly diagnosed and followed up every 3 months from the day they were discharged from the hospital. Follow up period is at least 1 year from last day of chemotherapy. Clinical data included patient demographics, radiological and characteristics; whole brain volume (mm2) calculated from BainLabTM automatically, Global Cortical Atrophy (GCA) for global brain atrophy, Medial Temporal Atrophy (MTA) for temporal atrophy, and Fazekas scale for white matter lesions. The unpaired t test and multivariable liner regression were used to examine the clinical, CSF and radiological characteristics of patients. The mean age at symptom onset was 65.2 years (47-85 years). Thirty three of 53 (62%) patients underwent WBRT with chemotherapy (WBRT group). In all patients, multivariable analysis revealed WBRT correlate with brain volume reduction (p=0.0005) and progression of temporal lobe atrophy (p=0.0056). In addition, Age correlated with increasing white matter lesions at 1 year after chemotherapy (p=0.0422). In WBRT group, multivariable analysis indicated that high CSF IL-10 level accelerated brain volume reduction (p=0.0122) and temporal lobe atrophy (p=0.0343) at 6 months after chemotherapy. However, there were no significant factor for influencing brain atrophy at 1 year. Higher IL-10 ( &amp;gt; 100mg/ml) level demonstrated higher brain atrophy rate (p=0.0366) and severe temporal atrophy at 1 year (p=0.0214). In elderly patients with high preoperative CSF IL-10 levels, cerebral atrophy and toxic leukoencephalopathy may progress in short period of time after WBRT. We should consider treatment strategy that avoid WBRT, such as R-MPV chemotherapy, for PCNSL patients.
DNAR-14. Y-BOX BINDING PROTEIN 1 REGULATES MEDULLOBLASTOMA TUMOR BIOLOGY AND THERAPEUTIC RESPONSE
Authors: Leon McSwain, Victor Chen, Tiffany Huang, Grace Zhou, Anna Kenney
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Medulloblastoma (MB) is the most common pediatric brain tumor. MB can be dividing into 4 genetically distinct subgroups (Sonic Hedgehog (SHH), Wingless (WNT), Group 3, and Group 4). Most patients receive radiation and cisplatin backbone therapy. SHH and Group3 patients demonstrate poor prognosis, especially in cases of MYC amplification or p53 mutation. Given the continued reliance on DNA damage therapies, and our groups previous findings that YB1 regulates IGF2 transcription in SHH MB, we chose to investigate the role of YB1 in the DNA damage response and we performed RIPseq to understand mRNAs regulated by YB1 that may be targeted as novel therapeutics. METHODS Cell lines include primary MBCs derived from NeuroD2-SmoA1 SHH mice, ONS-76 human SHH, Daoy human SHH, D341 and D425 Human Group 3. YB1 overexpression or knockdown followed by radiation and assessment of yH2AX (a marker of DNA de-condensation following damage), Comet assay (a marker of physical damage), and proliferation time courses were used to assess effects of YB1 modulation on radiation response. RIPseq and YB1 knockdown were used to assess the effects of YB1 on PLXND1 levels. Scratch assay and western blotting of EMT markers were used to assess effects of PLXND1 silencing on migration. RESULTS (Radiation Studies) Overexpression of YB1 in primary MBCs followed by allograft into BL6 mice results in decreased overall survival. YB1 silencing followed by radiation results in faster resolution of yH2AX, faster resolution of damage, and lack of pRPA32 accumulation. YB1 silencing sensitizes cells to radiation resulting in substantial decreases in proliferation. (RNA Binding Protein Studies) YB1 binds and positively regulates PLXND1 translation. Silencing PLXND1 results in decreased migration and EMT mark expression. CONCLUSIONS YB1 drives a more error prone non-homologous End-Joining based mechanism of repair and binds and regulates PLXND1 post-transcriptionally. PLXND1 drives a migratory phenotype in SHH MB.
QLTI-12. THE IMPACT OF MENTORING ON EARLY CAREER FACULTY: ASSESSMENT OF A VIRTUAL MENTORING PROGRAM
Authors: Akanksha Sharma, Heather Leeper, Soo Bang, Donna Molaie, Alyx Porter
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Participation in mentorship programs for early career physicians is crucial to developing key skills and professional networks, but availability and opportunities for mentorship may be hampered by racial, ethnic and gender leadership disparities in medicine. A 6-month virtually facilitated peer mentorship program for women and diverse early career faculty was developed and piloted through the Society for Neuro-Oncology (SNO) Women &amp; Diversity Committee. METHODS We designed and conducted a 6-month pilot open to SNO’s multidisciplinary early career members, leveraging peer-mentoring sessions with mid-to late-career physician mentors. A curriculum with online resources was provided and group assignments were based on time-zones and interests. Pre- and post-participation surveys assessed mentee experience and descriptive statistics assessed participant demographics and survey results. Results/ CONCLUSION Twenty mentee applicants participated in 5 groups. Mentees were 90% women, 60% from diverse racial and ethnic backgrounds. Most were aged 31-40 (75%) and junior faculty (50%) in neuro-oncology (65%). Five mentors (2 female) practiced either neuro-oncology (3), neurosurgery (1) or radiation oncology (1). The proportion of mentees with a signature talk increased from 15% to 71% during the pilot. A large majority (64%) reported a positive impact of the program on their profile, career and networking, and reported participation was worthwhile (86%), and worth recommending to others (93%). Feedback themes included personal growth, peer support, networking, job opportunities, desire for late career female mentors, and scheduling constraints. The virtual environment during a global pandemic allowed participants to connect, creating a venue to discuss topics such as work-life balance, burnout, and self-advocacy. We did not have 100% post pilot follow up despite multiple attempts, limiting complete understanding of the pilot. This virtual mentorship pilot program proved feasible and of value in development of early career women and diverse individuals. A resource toolkit has been designed to scale and diffuse.
NIMG-65. IMPROVED SPATIAL MAPPING OF TUMOR AGGRESSIVENESS WITH 1H MAGNETIC RESONANCE SPECTROSCOPY AND DEEP LEARNING IN PATIENTS WITH NEWLY-DIAGNOSED GLIOMA
Authors: Nate Tran, Yan Li, Jacob Ellison, Oluwaseun Adegbite, Joanna J Phillips, Annette Molinaro, Valentina Pedoia, Anny Shai, Devika Nair, Angela Jakary, Marisa Lafontaine, Javier Villanueva-Meyer, Mitchel S Berger, Shawn L Hervey-Jumper, Manish Aghi, Susan M Chang, Janine Lupo
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Noninvasive, radiopathomic mapping of tumor aggressiveness can benefit patients with glioma by guiding the selection of tissue samples for diagnosis, increasing extent of resection, and non-invasively characterizing residual tumor burden for subsequent treatment. Although prior studies have demonstrated the utility of metabolic metrics quantified from 1H-MR Spectroscopy (MRS) in probing tumor pathology, this study evaluated the benefit of using the entire 1D-spectrum and deep learning for radiopathomic mapping of intratumoral cellularity, proliferation (ki-67), and a new tumor aggressiveness index (TAI) defined as log((n(ki−67)+n(cellularity))*tumor-score). METHODS Multi-voxel 1H-MRS was acquired on 281 patients newly diagnosed with a glioma (47% IDH-wildtype) immediately before surgical resection. After reconstructing individual spectra at the locations where tissue samples were obtained during surgery and normalizing by NAA in contralateral normal-appearing-white-matter, 607 spectra with corresponding histopathology were deemed of sufficient quality for analysis. A 1D convolutional-neural-network with bidirectional long- and short-term memory deep-learning model using the entire spectrum (0.6-3.6ppm) was compared to mixed-effects regression (with choline-to-NAA index[CNI]) and Random Forest (with CNI+normalized peak heights) models for predicting ki-67, cellularity, and TAI. Results &amp; DISCUSSION Using deep-learning on the entire spectrum resulted in 10.3%-22.1% lower mean absolute error (MAE) and 0.32-0.37 higher R2 values compared to using CNI alone or a random forest model with multiple metabolic metrics. MAE values for all 3 deep-learning models were 26-44% &amp;lt; 1 standard deviation of the ground truth, demonstrating reasonable prediction accuracy within the test data set. Although the lowest MAE (0.16) and highest R2 (0.41) was attained when predicting TAI with deep-learning, the prediction of cellularity resulted in the lowest %MAE. Colormaps of predicted pathology identified regions of heightened aggressiveness surrounding tissue samples with most abnormal pathological features that sometimes extended beyond the non-enhancing lesion. Current work is evaluating the clinical utility of our deep-learning model and predicted maps of aggressiveness.
TMIC-18. ROLE OF DISCOIDIN DOMAIN RECEPTORS (DDR1/DDR2) IN SENSITIZATION OF GLIOMAS TOWARDS RADIOTHERAPY
Authors: Mohammad Faisal Syed, Andrea Comba, Maria Luisa Varela, Anna Argento, Emily Brumley, Clifford Abel, Maria Castro, Pedro Lowenstein
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM), a high-grade glial tumor, is highly aggressive and is characterized by intra-tumoral heterogeneity and widespread infiltration, impairing therapeutic success. Our laboratory discovered dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal features called “oncostreams” inside GBM tumors that facilitate invasion into the normal brain. We found that collagen 1α1 (Col1A1) is essential for oncostream structure and function. Using in vivo intravital imaging and ex vivo explant glioma models, we established that Col1A1 suppression abolishes oncostreams, reprograms the malignant histopathological phenotype, and extends median survival in mice. However, the signaling through which collagen communicates to maintain an invasion-permissive glioma tumor microenvironment remains unclear. We propose to analyze a poorly understood collagen receptor family -the discoidin domain receptors (DDRs) - which is expressed in glioma and perivascular stromal cells. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) data suggest DDR1/DDR2 overexpression correlates with tumor progression and poor prognosis in glioma patients. Our RNA-seq data further confirm overexpression of DDRs in NPA and NPD glioma compared to the normal brain. Our preliminary data suggests that inhibiting collagen receptors DDR1 or DDR2 sensitizes glioma cells to radiotherapy (IR). DDR1 inhibition completely disrupts oncostreams` structure in the ex vivo explant glioma model. Moreover, pharmacological inhibition of DDR1 combined with irradiation significantly enhances the median survival of NPA (Nras, shP53, shATRX) tumors in an orthotopic mouse glioma model. Furthermore, we are currently testing whether inhibition of DDR1 using a genetically engineered mouse model (GEMM) of glioma called NPAD1 (Nras, shP53, shATRX, shDDR1) will show an increase in overall survival. We hypothesize that blocking collagen receptors DDR1 or DDR2 will control tumor growth, invasion and mediate anti-glioma immunity. This study will eventually uncover a novel therapeutic treatment for GBM, targeting DDR1 and DDR2 in human patients.
NIMG-35. THE DEEP TOPOLOGY OF GLIOMAS
Authors: James Ruffle, Samia Mohinta, Sebastian Brandner, Harpreet Hyare, Parashkev Nachev
Journal: Neuro-Oncology (2022)

Abstract Tumor heterogeneity is increasingly recognized as a major obstacle to therapeutic innovation in neuro-oncology. Gliomas typically exhibit a spectrum of genetic mutations, reflecting multiple, potentially complex molecular interactions, and vary widely in their imaging appearances across size, morphology, texture, anatomical distribution, and many other spatial properties. This multifaceted diversity obscures the relationship between tumor genotypic and imaging features, and their joint influence on disease evolution and treatment susceptibility. Though opaque to simple statistical methods, it may nonetheless be accessible to models with the expressivity to capture complex interactions between many different factors. Studying an international sample of 4064 IDH-wildtype glioblastoma, IDH-mutant oligodendroglioma and astrocytoma, here we develop a highly expressive modelling framework based on deep learning and Bayesian models of networks with the power to capture the multimodal heterogeneity of glioma. We map the characteristic distribution of tumor tissue components across the brain, and link their spatial properties to regional connectivity, normal gene expression, and tumor genetics. We derive a hierarchical anatomical representation of these multimodal patterns of variation, and quantify their comparative functional impact by reference to meta-analytic maps of brain function. Our results reveal the deep topological structure of gliomas, enabling richer, more closely individuating phenotyping, the development of more robust predictive models of treatment and prognosis, and illuminating multimodal associations of potential mechanistic significance.
EXTH-30. PHARMACOKINETICS- AND PHARMACODYNAMICS-BASED EVALUATION OF QUISINOSTAT AS A RADIOSENSITIZER IN PRECLINICAL MODELS OF GBM
Authors: Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna Melendez, James McNamara, William Knight, Connor White, Zorana Opachich, Niddhi Ganta, Alexis Giff, Nader Sanai, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. Class I HDACs mediate chromatin compaction and are frequently overexpressed in GBM. Hence, there has been considerable interest in HDAC inhibitors (HDACi) for the treatment of malignant brain tumors. However, to date almost all HDACi tested clinically have failed to provide significant therapeutic benefit to primary and recurrent GBM patients. These HDACi are broad-spectrum with poor or unknown pharmacokinetic profiles and narrow therapeutic window. Isoform specificity for HDACi is important given that not all HDAC enzymes are equally expressed in GBM. Recently, we uncovered the functional importance of HDAC1 in therapy-resistant glioma stem cells, where we found that its expression increases with brain tumor grade and is correlated with decreased survival. While no class I HDAC isoform-specific inhibitors are currently available, the second-generation HDACi quisinostat harbors high specificity for HDAC1. In this study, we assessed the pharmacokinetic, pharmacodynamic and radiation-sensitizing properties of quisinostat in preclinical models of human GBM. In vitro analyses conducted in patient-derived glioma stem cell (GSC) lines revealed that quisinostat exhibited potent growth inhibition, induced global histone hyperacetylation, elevated DNA damage, cell death and cell cycle arrest. To determine the efficacy and drug distribution profile of quisinostat in vivo, athymic mice with orthotopic or flank tumors were treated with an optimized treatment schedule. At various timepoints during treatment, plasma and brain/tumor tissue were collected to measure total and unbound drug levels by liquid chromatography tandem mass spectrometry (LC-MS/MS), coupled with transcriptomic and pharmacodynamic analyses of tumor tissues. We demonstrate quisinostat is a brain-penetrant molecule that reduces tumor burden in flank and orthotopic models of GBM, and significantly extends survival when administered with radiation. Together, these results provide a rationale for developing quisinostat as a potential combination therapy with radiation for the treatment of GBM.